Treating cancer with small molecules that inhibit acss-2

Abstract

Cancers develop specific metabolic adaptations such as the opportunistic utilization of acetate as an alternative carbon source and the generation of acetyl-CoA mediated by ACSS-2, which is upregulated in response to nutrient and hypoxic stress. This pathway can fuel various processes involving acetyl-CoA, including de novo fatty acid synthesis and protein acetylation. Provided herein are methods of treating a cancerous disease in a subject using compounds that inhibit ACSS-2.

1 . A method of treating a cancerous disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of any one or more of the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the cancerous disease is a brain cancer. 
     
     
         3 . The method of  claim 2 , wherein the brain cancer is a brain metastasis. 
     
     
         4 . The method of  claim 3 , wherein the brain metastasis is a breast cancer brain metastatic tumor. 
     
     
         5 . The method of  claim 2 , wherein the compound crosses the blood-brain barrier. 
     
     
         6 . The method of  claim 1 , wherein the cancerous disease is breast cancer. 
     
     
         7 . The method of  claim 1 , wherein the compound inhibits and/or inactivates acyl-coenzyme A synthetase short-family member 2 (ACSS-2). 
     
     
         8 . The method of  claim 1 , wherein growth of the cancerous disease is inhibited. 
     
     
         9 . The method of  claim 1 , further comprising administering radiation therapy to the subject. 
     
     
         10 . The method of  claim 9 , wherein the radiation therapy is directed to a tumor. 
     
     
         11 . A method of inhibiting and/or inactivating acyl-coenzyme A synthetase short-family member 2 (ACSS-2), the method comprising contacting the ACSS-2 with of any one or more of the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of  claim 11 , wherein the inhibiting and/or inactivating is done in vitro. 
     
     
         13 . The method of  claim 11 , wherein the inhibiting and/or inactivating comprises administering the one or more compounds to a subject. 
     
     
         14 . The method of  claim 13 , wherein the inhibiting and/or inactivating results in inhibited growth of a cancerous disease in the subject.